There is still a need in the art for cytotoxic agents for use in cancer therapy. In particular, there is a need for cytotoxic agents which inhibit or treat the growth of tumors which have an effect similar to paclitaxel and interfere with the process of microtubule formation. Additionally, there is a need in the art for agents which accelerate tubulin polymerization and stabilize the assembled microtubules.
Antimicrotubule drugs are a major category of anticancer agents (Rowinsky, E. K., and Tolcher, A. W. Antimicrotubule agents. In: V. T. Devita, Jr., S. Hellman, and S. A. Rosenberg (eds.), Cancer Principles and Practice, Ed. 6, pp. 431-452. Philadelphia: Lippincott Williams and Wilkins, 2001). Antimicrotubule drugs work by interfering with the function of cellular microtubules, particularly the mitotic spindle. The disruption of normal spindle function leads to apoptotic cell death.
Many tumors are inherently resistant (e.g., colon tumors) or become resistant after multiple cycles of treatment, at least in part due to the expression of drug transporters located in cancer cell membranes that pump the drugs out of cells and thereby decrease their efficacy (Gottesman, M. M. Mechanisms of cancer drug resistance. Annu. Rev. Med., 53: 615-627, 2002). The best known of these transporters is P-glycoprotein. Accordingly, there is a need for new agents with taxane-like effects on microtubule polymerization that are not substrates of P-glycoprotein or other such pumps and that therefore will overcome this cause of taxane resistance in patients.
It is an advantage to provide new compounds which provide a method of treating or inhibiting cell proliferation, neoplastic growth and malignant tumor growth in mammals by administering compounds which have paclitaxel like anticancer activity. It is an additional advantage to provide new compounds which provide a method for treating or inhibiting growth of cancerous tumors that express multiple drug resistance (MDR) or are resistant because of MDR. It is an additional advantage to provide new compounds which provide a method of treating or inhibiting the growth of cancerous tumors in a mammal with inherent or acquired resistance to chemotherapeutic agents and in particular antimitotic agents.
Accordingly, while there is ongoing research for new clinical candidates there is also a search for new and improved methods of preparation of those selected clinical candidates.
Described in WO 02/02563 A2 is the use of triazolopyrimidines having the structural formula
in cancer therapy, and in particular as microtubule agents. Previously described in U.S. Pat. Nos.: 5,593,996; 5,756,509; 5,948,783; 5,981,534; 5,612,345; 5,994,360; 6,020,338; 5,985,883; 5,854,252; 5,808,066; 5,817,663; 5,955,252; 5,965,561; 5,986,153; 5,750,766; 6,117,876; 6,297,251 and International Publication Numbers: WO98/46607; WO98/46608; WO99/48893; WO99/41255; EPO 834513A2; EPO 782997A2; EPO550113B1; FR2784381A1; EPO 989130A1; WO98/41496; WO94/20501; EPO 945453A1; EPO 562615A1; EP 077065 and EPO 562615B1 are the methods of preparation and the use of the above triazolopyrimidines in agriculture as fungicides.
Described in copending application No. 60/505,544, filed Sep. 24, 2003 is a series of 6-[(substituted)phenyl]-triazolopyrimidine compounds having the structural formula
which are microtubule inhibitors and useful in the treatment of cancer.
Often, a process which works in the laboratory is not practical for large-scale preparations. In particular, the reported synthesis of 5,7-dichloro-6-(substituted-phenyl)-[1,2,4]triazolo[1,5-a]pyrimidine prepared by cyclization of 2-(substituted-phenyl)-malonic acid diethyl ester with 1-amino-2,3,5-triazole is described in U.S. Pat. No. 6,117,876 and further described in EP 0 770 615 A1 and EP 0 770 615 B1 where 6-(substituted-phenyl)-[1,2,4]triazolo[1,5-a]pyrimidine-5,7-diol is formed and chlorinated by reaction with phosphorus oxychloride to give 5,7-dichloro-6-(substituted-phenyl)-[1,2,4]triazolo[1,5-a]pyrimidine. While the described series of steps may be completed on a small scale in a single vessel, the addition of chlorinating reagent, phosphorous oxychloride at 130° C. following removal of ethanol by distillation, is difficult to perform in large-scale preparations. Further the above described process is limited to small-scale synthesis because the resulting product as an oil is difficult to purify.
U.S. Pat. No. 5,986,135 and U.S. Pat. No. 6,117,876 describe a method for the preparation of [5-chloro-6-(substituted-phenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]-((1S)-2,2,2-trifluoro-1-methyl-ethyl)-amine, through amination of 5,7-dichloro-6-(substituted-phenyl)-[1,2,4]triazolo[1,5-a]pyrimidine with (S)-2,2,2-trifluoro-1-methyl-ethylamine. The method however is not entirely satisfactory because an oily intermediate, which lacks a practical method of purification, is formed when preparing the 5,7-dichloro-6-(substituted-phenyl)-[1,2,4]triazolo[1,5-a]pyrimidine and further the subsequent reaction with (S)-2,2,2-trifluoro-1-methyl-ethylamine is performed.
Clearly there is need to provide a new process for the preparation of 6-[(substituted)phenyl]-triazolopyrimidine compounds which overcomes the drawbacks of the prior art processes. In particular, there is a need for a process to prepare purified crystalline 6-[(substituted)phenyl]-triazolopyrimidine compounds.
Further there is a need to provide a new process which in comparison with those described in the above mentioned art represents a significant advance over the art.
In light of the usefulness of the triazolopyrimidine compounds in cancer therapy, there is a need to develop simpler and milder methods for their preparation.